The causes of types I and II diabetes are not yet clear, although both genetics and environment seem to be the factors. Type I is an autonomic immune disease and patient must take insulin to survive. Type II diabetes is more common form is a metabolic disorder resulting from the body's inability to make a sufficient amount of insulin or to properly use the insulin that is produced. Insulin secretion and insulin resistance are considered the major defects, however, the precise genetic factors involved in the mechanism remain unknown.
Patients with diabetes usually have one or more of the following defects:
Less production of insulin by the pancreas;
Over secretion of glucose by the liver;
Independent of the glucose uptake by the skeletal muscles;
Defects in glucose transporters, desensitization of insulin receptors; and
Defects in the metabolic breakdown of polysaccharides.
Other than the parenteral or subcutaneous administration of insulin, there are about four classes of oral hypoglycemic agents used i.e. sulfonylurea, biguanides, alpha glucosidase inhibitors and thiazolidinediones.
Each of the current agents available for use in treatment of diabetes has certain disadvantages. Accordingly, there is a continuing interest in the identification and development of new agents, which can be orally administered, for use in the treatment of diabetes.
The thiazolidinedione class listed above has gained more widespread use in recent years for treatment of type II diabetes, exhibiting particular usefulness as insulin sensitizers to combat “insulin resistance”, a condition in which the patient becomes less responsive to the effects of insulin. There is a continuing need for nontoxic, more widely effective insulin sensitizers.
Inducible nitric oxide synthase (iNOS, also termed NOS2), whose expression is regulated by IKKβ-NF-κB, is assumed to be one of the candidates that mediate inflammation-involved insulin resistance. Accumulating evidence indicates a close link between iNOS and insulin resistance. Although iNOS was originally identified in macrophages, it is now known that it is widely expressed in many tissues, including insulin-sensitive organs such as skeletal muscle, adipose tissue, and liver, in normal rodents and humans (Fujimoto et al Diabetes, 2005, 54, 1340). The expression of iNOS is up regulated by most, if not all, inducers of insulin resistance, including proinflammatory cytokines, obesity, free fatty acids, hyperglycemia, endotoxins, and oxidative stress. In fact, elevated expression of iNOS was observed in skeletal muscle of high-fat diet fed mice, in heart of Zucker diabetic fatty rats, and in skeletal muscle and platelets of patients with type II diabetes. Nitrosative protein modifications, such as tyrosine nitration often associated with iNOS expression, were elevated in plasma, skeletal muscle, vasculature and retina of patients with and rodent models of type II or obesity-related diabetes. Furthermore, iNOS induction resulted in attenuated insulin-stimulated glucose uptake in cultured skeletal muscle cells.
Recent advances in scientific understanding of the mediators involved in acute and chronic inflammatory diseases and cancer have led to new strategies in the search for effective therapeutics. Traditional approaches include direct target intervention such as the use of specific antibodies, receptor antagonists, or enzyme inhibitors. Recent breakthroughs in the elucidation of regulatory mechanisms involved in the transcription and translation of a variety of mediators have led to increased interest in therapeutic approaches directed at the level of gene transcription.
As indicated above, the present invention is also concerned with treatment of immunological diseases or inflammation, notably such diseases as are mediated by cytokines or cyclooxygenase. The principal elements of the immune system are macrophages or antigen-presenting cells, T cells and B cells. The role of other immune cells such as NK cells, basophils, mast cells and dendritic cells are known, but their role in primary immunologic disorders is uncertain. Macrophages are important mediators of both inflammation and providing the necessary “help” for T cell stimulation and proliferation. Most importantly macrophages make IL 1, IL 12 and TNF-α all of which are potent pro-inflammatory molecules and also provide help for T cells. In addition, activation of macrophages results in the induction of enzymes, such as cyclooxygenase II (COX-2), inducible nitric oxide synthase (iNOS) and production of free radicals capable of damaging normal cells. Many factors activate macrophages, including bacterial products, superantigens and interferon gamma (IFN γ). It is believed that phosphotyrosine kinases (PTKs) and other undefined cellular kinases are involved in the activation process.
Cytokines are molecules secreted by immune cells that are important in mediating immune responses. Cytokine production may lead to the secretion of other cytokines, altered cellular function, cell division or differentiation. Inflammation is the body's normal response to injury or infection. However, in inflammatory diseases such as rheumatoid arthritis, pathologic inflammatory processes can lead to morbidity and mortality. The cytokine tumor necrosis factor-alpha (TNF-α) plays a central role in the inflammatory response and has been targeted as a point of intervention in inflammatory disease. TNF-α is a polypeptide hormone released by activated macrophages and other cells. At low concentrations, TNF-α participates in the protective inflammatory response by activating leukocytes and promoting their migration to extravascular sites of inflammation (Moser et al., J Clin Invest, 83:444-55, 1989). At higher concentrations, TNF-α can act as a potent pyrogen and induce the production of other pro-inflammatory cytokines (Haworth et al., Eur J Immunol, 21:2575-79, 1991; Brennan et al., Lancet, 2:244-7, 1989). TNF-α also stimulates the synthesis of acute-phase proteins. In rheumatoid arthritis, a chronic and progressive inflammatory disease affecting about 1% of the adult U.S. population, TNF-α mediates the cytokine cascade that leads to joint damage and destruction (Arend et al., Arthritis Rheum, 38:151-60, 1995). Inhibitors of TNF-α, including soluble TNF receptors (etanercept) (Goldenberg, Clin Ther, 21:75-87, 1999) and anti-TNF-α antibody (infliximab) (Luong et al., Ann Pharmacother, 34:743-60, 2000), have recently been approved by the U.S. Food and Drug Administration (FDA) as agents for the treatment of rheumatoid arthritis.
Elevated levels of TNF-α have also been implicated in many other disorders and disease conditions, including cachexia, septic shock syndrome, osteoarthritis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis etc.
Thus it can be seen that inhibitors of TNF-α are potentially useful in the treatment of a wide variety of diseases. While there have been prior efforts to provide compounds for inhibiting TNF-α, IL-1, IL-6, COX-2 or other agents considered responsible for immune response, inflammation or inflammatory diseases, e.g., arthritis, there still remains a need for new and improved compounds for effectively treating and inhibiting such diseases.
The TNF-α has significant role in improvement of insulin resistance. It accelerates lipolysis and increases free fatty acid levels in the circulation. It down regulates synthesis of insulin receptor, insulin receptor substrate-1(IRS-1) and glucose transporter (GLUT-4). It increases phosphorylation of IRS-1 serine-threonine and phosphortyrosine phosphatase (PTPase) activity. It inhibits insulin receptor autophosphorylation, tyrosine phosphorylation of IRS-1, PPAR-γ synthesis and insulin-stimulated glucose transport.
With an objective to develop novel compounds for lowering blood glucose, free fatty acids, cholesterol and triglyceride levels in type II diabetes and to treat autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, we found that the compound 5-[4-(4-(2-amino-2-methoxycarbonylethyl)phenoxy)benzyl]-thiazolidin-2,4-dione hydrochloride salt, disclosed in commonly assigned U.S. Pat. No. 6,794,401, metabolizes to {4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acetic acid, which is within the scope of formula (I).
An object of the present invention is therefore to provide novel heterocyclic compounds of the general formula (I), derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof, as well as pharmaceutically acceptable compositions containing any of these singly or in combination.
Another object of the present invention is to provide methods using these compounds and compositions for treatment of disorders associated with insulin resistance, such as polycystic ovary syndrome, as well as hyperlipidemia, coronary artery disease and peripheral vascular disease, and for the treatment of inflammation and immunological diseases, particularly those mediated by cytokines such as TNF-α, IL-1, IL-6, IL-1β and cyclooxygenase such as COX-2. Mediation of cytokines such as TNFα may also provide methods of using such compounds for the treatment of cancer.
Another object of the present invention is to provide such compounds and compositions having enhanced activities, without toxic effect or with reduced toxic effect.